Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT14I72L)

• DOT Name: Tripartite motif-containing protein 59 (TRIM59)
• Synonyms: EC 2.3.2.27; RING finger protein 104; Tumor suppressor TSBF-1
• Gene Name: TRIM59
• UniProt ID: TRI59_HUMAN
• EC Number: 2.3.2.27
• Pfam ID: PF00643 ; PF13445
• Sequence:
  MHNFEEELTCPICYSIFEDPRVLPCSHTFCRNCLENILQASGNFYIWRPLRIPLKCPNCR
  SITEIAPTGIESLPVNFALRAIIEKYQQEDHPDIVTCPEHYRQPLNVYCLLDKKLVCGHC
  LTIGQHHGHPIDDLQSAYLKEKDTPQKLLEQLTDTHWTDLTHLIEKLKEQKSHSEKMIQG
  DKEAVLQYFKELNDTLEQKKKSFLTALCDVGNLINQEYTPQIERMKEIREQQLELMALTI
  SLQEESPLKFLEKVDDVRQHVQILKQRPLPEVQPVEIYPRVSKILKEEWSRTEIGQIKNV
  LIPKMKISPKRMSCSWPGKDEKEVEFLKILNIVVVTLISVILMSILFFNQHIITFLSEIT
  LIWFSEASLSVYQSLSNSLHKVKNILCHIFYLLKEFVWKIVSH
• Function: E3 ubiquitin ligase involved in different processes such as development and immune response. Serves as a negative regulator for innate immune signaling pathways by suppressing RLR-induced activation of IRF3/7 and NF-kappa-B via interaction with adapter ECSIT. Regulates autophagy through modulating both the transcription and the ubiquitination of BECN1. On the one hand, regulates the transcription of BECN1 through negatively modulating the NF-kappa-B pathway. On the other hand, regulates TRAF6-mediated 'Lys-63'-linked ubiquitination of BECN1, thus affecting the formation of the BECN1-PIK3C3 complex. In addition, mediates 'Lys-48'-linked ubiquitination of TRAF6 and thereby promotes TRAF6 proteasomal degradation. Acts also as a critical regulator for early embryo development from blastocyst stage to gastrula through modulating F-actin assembly and WASH1 'Lys-63'-linked ubiquitination.

Molecular Interaction Atlas (MIA) of This DOT

2 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Tripartite motif-containing protein 59 (TRIM59).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Tripartite motif-containing protein 59 (TRIM59).	[9]

12 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Tripartite motif-containing protein 59 (TRIM59).	[2]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Tripartite motif-containing protein 59 (TRIM59).	[3]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Tripartite motif-containing protein 59 (TRIM59).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of Tripartite motif-containing protein 59 (TRIM59).	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Tripartite motif-containing protein 59 (TRIM59).	[4]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Tripartite motif-containing protein 59 (TRIM59).	[6]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Tripartite motif-containing protein 59 (TRIM59).	[7]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Tripartite motif-containing protein 59 (TRIM59).	[8]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Tripartite motif-containing protein 59 (TRIM59).	[10]
Geldanamycin	DMS7TC5	Discontinued in Phase 2	Geldanamycin increases the expression of Tripartite motif-containing protein 59 (TRIM59).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Tripartite motif-containing protein 59 (TRIM59).	[12]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Tripartite motif-containing protein 59 (TRIM59).	[13]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [3] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [4] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [5] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [6] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [7] In vitro effects of aldehydes present in tobacco smoke on gene expression in human lung alveolar epithelial cells. Toxicol In Vitro. 2013 Apr;27(3):1072-81.
• [8] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [9] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [10] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [11] Identification of transcriptome signatures and biomarkers specific for potential developmental toxicants inhibiting human neural crest cell migration. Arch Toxicol. 2016 Jan;90(1):159-80.
• [12] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [13] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.